Method for Non-Invasive Brain Stimulation

ABSTRACT

Magneto-electric nanoparticles in a subject interact with an external magnetic field to cause stimulation of neural networks in the subject. Electric signals in the neural network are coupled to magnetic dipoles induced in the nanoparticles to cause changes in electric pulse sequences of the subject&#39;s brain.

CROSS-REFERENCE TO RELATED APPLICATIONS

This applications claims the benefit of priority under 35 U.S.C. §119(e)of U.S. Provisional Patent Application No. 61/650,314, filed May 22,2012, which is incorporated herein by reference in its entirety and forall purposes.

STATEMENT REGARDING FEDERAL RESEARCH

This invention was made with government support under: Department ofDefense (DoD) Defense Microelectronics Activity (DMEA) contract#H94003-09-2-0904; National Science Foundation (NSF) award #005084-002;National Institute of Health (NIH) DA #027049; University of California(UC) Discovery Grant #189573; and Florida Scholars Boost Award#212400105. The government has certain rights in the invention.

FIELD OF THE DISCLOSURE

The present disclosure relates to methods of artificially andnon-invasively stimulating neural activity in the brain and,specifically, to methods using magneto-electric nanoparticles.

BACKGROUND

The background description provided herein is for the purpose ofgenerally presenting the context of the disclosure. Work of thepresently named inventors, to the extent it is described in thisbackground section, as well as aspects of the description that may nototherwise qualify as prior art at the time of filing, are neitherexpressly nor impliedly admitted as prior art against the presentdisclosure.

The ability to monitor and affect signaling within a neural network and,in particular, within the brain remains an area of research that hasbroad potential implications in medicine and neural engineering. Withinthe medical realm, for example, brain stimulation has been shown torelieve and/or prevent symptoms associated with a variety of conditionsincluding, for example, infections, trauma, stroke and other vascularconditions, seizures, tumors, and various neurodegenerative conditionssuch as Parkinson's disease, Alzheimer's diseases, multiple sclerosis,and others.

The signaling in a biological neural network is based on a highlycollective system of electric charges, neurotransmitters and actionpotentials. The ability to reliably and non-invasively incite andmonitor the neuronal charge excitations from outside with the purpose ofartificially stimulating the neural network remotely remains animportant roadblock to enable advances in the detection, monitoring, andtreatment of neurological and related conditions. A neural network canbe considered as a complex electrical circuit made of many neuronsconnected through synapses formed between axons and dendrites. Bothtypes of synapses, known as chemical and electrical synapses,respectively, transfer information between adjacent axons and dendritesdirectly or indirectly through electric field energy. Consequently, theneural network is sensitive to external electric fields. Moreover, theability to efficiently control the network at the micro- or nano-scalecan enable unprecedented control of important brain functions. Existingtechnology typically relies on invasive direct-contact-electrodetechniques such as Deep Brain Stimulation (DBS), which is one of only afew neurosurgical methods allowed for blinded studies. Existingnon-invasive brain stimulation methods include repetitive trans-cranialmagnetic stimulation (rTMS) and trans-cranial direct current stimulation(tOCS). rTMS and tDCS represent major advances of the state of the artin non-invasive brain stimulation, but the depth and locality focusingare limited in both methods. In rTMS, high intensity magnetic fields arerequired to stimulate deep brain regions but high intensity magneticfields may lead to undesirable side effects.

SUMMARY

In an embodiment, a method of non-invasively stimulating a neuralnetwork in a subject brain includes injecting the subject with asolution including nanoparticles formed from a multiferroic material andcausing an alternating current magnetic field directed toward thesubject to interact with the nanoparticles to induce local electriccharge oscillations in the nanoparticles. In some embodiments, thesolution is an aqueous solution and, in embodiments, the nanoparticlesare magneto-electric nanoparticles. The solution has a concentration of3×10⁶ nanoparticles per cubic centimeter, in some embodiments. Themagnetic field may be directed at a specific region of the subject brainand, in embodiments, the frequency of the magnetic field may be selectedaccording to a frequency associated with electric signals in thespecific region of the subject brain. In an embodiment, the frequency is80 Hz. The nanoparticles are less than 50 nm in size, in embodiments,and are 20 nm in size in some embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A illustrates typical electric pulse sequences triggered in thethalamic area of the brain of a healthy person;

FIG. 1B illustrates typical electric pulse sequences triggered in thesubthalamic nucleus of the brain of a healthy person;

FIG. 1C illustrates typical electric pulse sequences triggered in theglobus pallidus of the brain of a healthy person;

FIG. 1D illustrates typical electric pulse sequences triggered in themedial globus pallidus of the brain of a healthy person;

FIG. 2A illustrates typical electric pulse sequences triggered in thethalamic area of the brain of a person suffering from Parkinson'sDisease;

FIG. 2B illustrates typical electric pulse sequences triggered in thesubthalamic nucleus of the brain of a person suffering from Parkinson'sDisease;

FIG. 2C illustrates typical electric pulse sequences triggered in theglobus pallidus of the brain of a person suffering from Parkinson'sDisease;

FIG. 2D illustrates typical electric pulse sequences triggered in themedial globus pallidus of the brain of a person suffering fromParkinson's Disease;

FIG. 3 illustrates the use of an electro-magnetic coil to causenanoparticles to generate electric fields in a subject brain accordingto the present description;

FIG. 4A illustrates modified electric pulse sequences triggered in thethalamic area of the brain of a person suffering from Parkinson'sDisease when treated with the present method;

FIG. 4B illustrates modified electric pulse sequences triggered in thesubthalamic nucleus of the brain of a person suffering from Parkinson'sDisease when treated with the present method;

FIG. 4C illustrates modified electric pulse sequences triggered in theglobus pallidus of the brain of a person suffering from Parkinson'sDisease when treated with the present method; and

FIG. 4D illustrates modified electric pulse sequences triggered in themedial globus pallidus of the brain of a person suffering fromParkinson's Disease when treated with the present method.

DETAILED DESCRIPTION

A method according to the present disclosure facilitates non-invasivestimulation and/or monitoring of signaling pathways in the brain usingmagneto-electric (ME) nanoparticles. ME materials include a sub-group ofmultiferroic materials having the ability to couple magnetic andelectric fields at room temperature. In contrast with electric fields,which are surface-limited and typically generated by invasive contactelectrodes, magnetic fields generated by ME nanoparticles can penetratethe entire brain non-invasively and be controlled using externallow-energy magnetic field sources.

FIGS. 1A-1D illustrate typical electric pulse sequences triggered infour regions of the brain of a healthy person, under normal conditions.FIG. 1A represents the electric pulse sequences generated in thethalamic area. FIG. 1B represents the electric pulse sequences generatedin the subthalamic nucleus (STN). FIG. 1C represents the electric pulsesequences generated in the globus pallidus (GPe). FIG. 1D represents theelectric pulse sequences generated in the medial globus pallidus (GPi).The four areas of the brain represented in the FIGS. 1A-1D areespecially important for understanding different stages of Parkinson'sDisease. In a healthy brain, such as that represented by the pulsesequences in FIGS. 1A-1D, the electric pulses are both periodic anduniform in amplitude, and do not display detectable lapses.

By contrast, FIGS. 2A-2D illustrate typical electric pulse sequencestriggered in the same four regions of the brain of a person sufferingfrom Parkinson's Disease. In FIGS. 2A-2D, the amplitude and periodicityof each pulse train, relative to those of the corresponding regions inFIGS. 1A-1D, is more or less the same. However, each pulse trainrepresented in FIGS. 2A-2D exhibits pronounced lapses 100 in theperiodic sequences. The effect is particularly noticeable in thethalamic region (FIG. 2A).

The methods described herein rely on the presence of ME nanoparticles inthe brain. The ME nanoparticles facilitate efficient coupling betweenmagnetic and electric fields at nanoscale (or microscale) over theentire brain volume. Once ME nanoparticles are present in the brain,remotely controlled magnetic fields (as opposed to electric fields) maybe used to induce strong local electric charge oscillations in the MEnanoparticles that, consequently, directly interact with the neuralnetwork. The interaction between the ME nanoparticles and the neuralnetwork can be used to induce localized and targeted brain stimulation.The magnetic fields generated by the ME nanoparticles can effectivelypenetrate the entire brain (if ME nanoparticles are present throughoutthe brain) non-invasively. The magnetic fields generated by the MEnanoparticles can be activated and deactivated remotely using externallow-energy magnetic field sources such as external electromagneticcoils.

The ME nanoparticles must be manufactured with certain properties forthe ME nanoparticles to be effective for use in monitoring orstimulating the neural network of the brain. For example, the MEnanoparticles be small enough to penetrate the blood-brain barrier. Inembodiments, the ME nanoparticles are smaller than approximately 50 nm,smaller than 40 nm, smaller than 35 nm, smaller than 30nm, smaller than25 nm, smaller than 20 nm, smaller than 15 nm, or smaller than 10 nm. Inembodiments, the ME nanoparticles have sizes in a range of 15-20 nm, ina range of 10-20 nm, in a range of 15-25 nm, in a range of 10-50 nm, ina range of 20-50 nm, in a range of 20-40 nm, or in a range of 10-30 nm.In any event, ME nanoparticles small enough to penetrate the blood-brainbarrier are able to move into selected brain regions and, accordingly,to effect stimulation or monitoring of said brain regions.

ME nanoparticles may be fabricated by chemical or physical methods,including, but not limited to, thermal decomposition, co-precipitation,and Ion Beam Proximity Lithography (IBPL). In IBPL, for example, a broadbeam of energetic (e.g., 20-50 keV) Helium ions illuminates a stencilmask (a thin membrane with etched windows) and the beamlets oftransmitted atoms write an array of nanoapertures into resist on asubstrate to transfer the mask pattern to the resist. Electrostaticfield deflection is used to replicate a sparse stencil mask into ahigh-density pattern of nanodots. The massively parallel nature of IBPLresults in practical throughputs necessary for fabricating large yieldsof nanoparticles.

Stencil masks with 100×100 cm² array of 20 nm diameter circular openingswith a 5 μm pitch can be fabricated using e-beam lithography. The arrayof sub-10 nm openings can be used to “write” high-density patterns ofnanoparticles to achieve a sub-10 nm linewidth, a 100 nm stencil maskcan be coated with a 40 nm scatter layer (e.g., gold) to effectivelyreduce the size of the stencil openings. Initially collimated atomsimpinging on a scatter layer are deflected and trapped within a 0.7 μmthick stencil channel.

In embodiments, the ME nanoparticles are suspended in an aqueoussolution and injected into the bloodstream of the patient. Because theME nanoparticles are small enough to penetrate the blood-brain barrier,the ME nanoparticles are able to move from the blood into the neuraltissue of the brain, whereby the ME nanoparticles may be “activated” byan external magnetic field. In embodiments, only a very low intensityexternal magnetic field is required to stimulate brain activity at anydepth in the brain. The external magnetic field generated, for example,by an electromagnetic coil, can be focused to act upon ME nanoparticlesin any particular region of the brain, in a manner illustrated generallyin FIG. 3. The external magnetic field generates alternating current(AC) signals in ME nanoparticles that are correlated with the frequencyspectrum of the neural charge activity, which in turn causes neurons inthe region to fire at similar frequencies. For example, provided thatthe ME nanoparticles have an adequately large magneto-electric couplingcoefficient, low-energy magnetic coils can be used to trigger thedesired stimulation, as described further below. In an embodiment, theME nanoparticles have a magneto-electric coupling coefficient of 100 Vcm⁻¹ Oe⁻¹.

The concentration of the solution of ME nanoparticles, and the amplitudeand frequency of the external AC magnetic field source, can be varied,in embodiments, to optimally stimulate the neural network. In anembodiment, an external AC magnetic field source generates a field withan amplitude of 300 oersted (Oe), and a frequency variable between 0 and1 kHz. Generally, the field amplitude should be sufficient to saturatethe ME nanoparticles during the stimulation procedure, and the fieldfrequency is selected according to the pulse frequency desired to begenerated in the targeted region. In an embodiment, the frequency of theAC magnetic field is 80 Hz.

An aqueous solution of ME nanoparticles has a concentration of between 0and 10⁷ particles per cubic centimeter, in embodiments and, in anembodiment, has a concentration of approximately 3×10⁶ particles percubic centimeter.

FIGS. 4A-4D represent electric pulse sequences triggered in the fourregions of the brain under study of a patient suffering from Parkinson'sDisease after treatment with the ME nanoparticles using a solutionhaving a concentration of 3×10⁶ particles per cubic centimeter, and astimulation frequency of 80 Hz (approximately the same frequency as theelectric pulse train in the thalamic region of a healthy person (seeFIG. 1A). The representation of FIG. 4A illustrates that the mostdramatically damaged signals in the Thalamic region are fully recovered,and partial recovery of the periodicity of other brain regions (FIGS.4B-4D) is also apparent.

Throughout this specification, plural instances may implementcomponents, operations, or structures described as a single instance.Although individual operations of one or more methods are illustratedand described as separate operations, one or more of the individualoperations may be performed concurrently and, unless specificallydescribed or otherwise logically required (e.g., a structure must becreated before it can be used), nothing requires that the operations beperformed in the order illustrated. Structures and functionalitypresented as separate components in example configurations may beimplemented as a combined structure or component. Similarly, structuresand functionality presented as a single component may be implemented asseparate components. These and other variations, modifications,additions, and improvements fall within the scope of the subject matterherein.

As used herein any reference to “one embodiment” or “ an embodiment”means that a particular element, feature, structure, or characteristicdescribed in connection with the embodiment is included in at least oneembodiment. The appearances of the phrase “in one embodiment” in variousplaces in the specification are not necessarily all referring to thesame embodiment.

As used herein, the terms “comprises,” “comprising,” “includes,”“including,” “has,” “having” or any other variation thereof, areintended to cover a non-exclusive inclusion. For example, a process,method, article, or apparatus that comprises a list of elements is notnecessarily limited to only those elements but may include otherelements not expressly listed or inherent to such process, method,article, or apparatus. Further, unless expressly stated to the contrary,“or” refers to an inclusive or and not to an exclusive or. For example,a condition A or B is satisfied by any one of the following: A is true(or present) and B is false (or not present), A is false (or notpresent) and B is true (or present), and both A and B are true (orpresent).

In addition, use of the “a” or “an” are employed to describe elementsand components of the embodiments herein. This is done merely forconvenience and to give a general sense of the description. Thisdescription should be read to include one or at least one and thesingular also includes the plural unless it is obvious that it is meantotherwise.

Upon reading this disclosure, those of skill in the art will appreciatestill additional alternative structural and functional designs for asystem and a process for identifying terminal road segments through thedisclosed principles herein. Thus, while particular embodiments andapplications have been illustrated and described, it is to be understoodthat the disclosed embodiments are not limited to the preciseconstruction and components disclosed herein. Various modifications,changes and variations, which will be apparent to those skilled in theart, may be made in the arrangement, operation and details of the methodand apparatus disclosed herein without departing from the spirit andscope defined in the appended claims.

We claim:
 1. A method of non-invasively stimulating a neural network ina subject brain, the method comprising: injecting the subject with asolution including nanoparticles formed from a multiferroic material;and causing an alternating current magnetic field directed toward thesubject to interact with the nanoparticles to induce local electriccharge oscillations in the nanoparticles.
 2. A method according to claim1, wherein injecting the subject with a solution comprises injecting thesubject with an aqueous solution.
 3. A method according to claim 1,wherein injecting the subject with a solution including nanoparticlesformed from a multiferroic material comprises injecting the subject witha solution including magneto-electric nanoparticles.
 4. A methodaccording to claim 1, wherein injecting the subject with a solutionincluding nanoparticles comprises injecting the subject with a solutionhaving a concentration of nanoparticles of 3×10⁶ nanoparticles per cubiccentimeter.
 5. A method according to claim 1, wherein causing analternating current magnetic field directed toward the subject tointeract with the nanoparticles comprises generating a magnetic fieldwith an electromagnetic coil.
 6. A method according to claim 1, whereincausing an alternating current magnetic field directed toward thesubject to interact with the nanoparticles comprises focusing themagnetic field on a specific region of the subject brain.
 7. A methodaccording to claim 6, wherein focusing the magnetic field on a specificregion of the subject brain comprises focusing the magnetic field on (a)the thalamic area; (b) the subthalamic nucleus; (c) the globus pallidus;or (d) the medial globus pallidus.
 8. A method according to claim 7,wherein causing an alternating current magnetic field directed towardthe subject to interact with the nanoparticles, further comprisesselecting a frequency of the alternating current magnetic fieldaccording to a frequency associated with electric signals in thespecific region of the subject brain.
 9. A method according to claim 1,wherein causing an alternating current magnetic field directed towardthe subject to interact with the nanoparticles comprises selecting afrequency of the alternating current magnetic field according to afrequency associated with electric signals in a specific region of thesubject brain.
 10. A method according to claim 1, wherein causing analternating current magnetic field directed toward the subject tointeract with the nanoparticles comprises causing an alternating currentmagnetic field having an amplitude of 300 Oe to interact with thenanoparticles.
 11. A method according to claim 1, wherein injecting thesubject with a solution including nanoparticles comprises injecting thesubject with a solution including nanoparticles having amagneto-electric coefficient of 100 V cm⁻¹ Oe⁻¹.
 12. A method accordingto claim 1, wherein injecting the subject with a solution includingnanoparticles comprises injecting the subject with a solution includingnanoparticles of 20 nm in size.
 13. A method according to claim 1,wherein injecting the subject with a solution including nanoparticlescomprises injecting the subject with a solution including nanoparticlesless than 50 nm in size.
 14. A method according to claim 1, whereininjecting the subject with a solution including nanoparticles comprisesinjecting the subject with a solution including nanoparticles formed byIon Beam Proximity Lithography.
 15. A method according to claim 1,wherein injecting the subject with a solution including nanoparticlescomprises injecting the subject with a solution including nanoparticlescomprises injecting a subject having Parkinson's Disease with a solutionincluding nanoparticles.
 16. A method according to claim 1, whereincausing an alternating current magnetic field directed toward thesubject to interact with the nanoparticles comprises causing analternating current magnetic field having a frequency of 80 Hz tointeract with the nanoparticles.